期刊
RAPID COMMUNICATIONS IN MASS SPECTROMETRY
卷 27, 期 1, 页码 35-50出版社
WILEY
DOI: 10.1002/rcm.6421
关键词
-
资金
- World Anti-Doping Agency (WADA) [11C8MT]
RATIONALE The efficiency of Sirtuin1, a major target for the treatment of various metabolic disorders such as inflammation and type 2 diabetes mellitus, can be modulated via low molecular mass SIRT1 activators (e.g. resveratrol, SRT1720, and SRT2104).The administration of such compounds results in increased deacetylation of substrates including p53, FOXO1, and PGC1alpha, potentially leading to an improved physical performance. Consequently, proactive and preventive anti-doping measures are required and an assay dedicated to serum and plasma was desirable. METHODS Model substances of emerging SIRT1 drug candidates were obtained and synthesized and their mass spectrometric behavior following positive or negative electrospray ionization and collision-induced dissociation was elucidated using low and high resolution/high accuracy (tandem) mass spectrometry. Subsequently, a screening and confirmation procedure necessitating 100 mu L of plasma was established employing liquid chromatography/tandem mass spectrometry (LC/MS/MS) based on diagnostic ion transitions recorded in multiple reaction monitoring mode. Sample preparation consisted of the addition of two deuterated internal standards (D8-SRT1720 and D4-resveratrol) to the plasma specimen and subsequent protein precipitation. RESULTS Characteristic product ions indicative of the core structures of the model analytes were characterized and utilized for the development of a multi-analyte LC/MS/MS detection method applicable to sports drug testing programs. The doping control assay was validated with regard to specificity, limits of detection (0.11 ng/mL), recoveries (9098%), intraday and interday precisions (218%), and ion suppression/enhancement effects. CONCLUSIONS The fragmentation pathways of SRT1720 and 4 SIRT1 activator models based on a common thiazole-imidazole nucleus as well as two different complementary activators (SIRT1 activator 3 and CAY10602), comprising a quinoxaline core, were studied. The resulting information was used to establish and validate a sports drug testing methodology relevant for an efficient and timely anti-doping procedure, targeting a new class of emerging therapeutics possessing significant potential for misuse in elite and amateur sport. Copyright (c) 2012 John Wiley & Sons, Ltd.
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